Isothiocyanate functional compounds augmented with secondary antineoplastic medicaments and associated methods for treating neoplasms

ABSTRACT

A formulation, including: (a) a first medicament, wherein the first medicament includes an isothiocyanate functional compound/surfactant; and (b) a second medicament, wherein the second medicament includes an antineoplastic agent, such as a cytotoxic antineoplastic agent and/or a targeted antineoplastic agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/793,337, entitled “ISOTHIOCYANATE FUNCTIONAL COMPOUNDS AUGMENTED WITHSECONDARY ANTINEOPLASTIC MEDICAMENTS AND ASSOCIATED METHODS FOR TREATINGNEOPLASMS” filed Feb. 18, 2020, now U.S. Pat. No. 10,765,656, which is acontinuation of U.S. application Ser. No. 16/595,983, entitled“ISOTHIOCYANATE FUNCTIONAL COMPOUNDS AUGMENTED WITH SECONDARYANTINEOPLASTIC MEDICAMENTS AND ASSOCIATED METHODS FOR TREATINGNEOPLASMS” filed Oct. 8, 2019, now U.S. Pat. No. 10,561,632, which is acontinuation of U.S. application Ser. No. 16/215,753, entitled“ISOTHIOCYANATE FUNCTIONAL COMPOUNDS AUGMENTED WITH SECONDARYANTINEOPLASTIC MEDICAMENTS AND ASSOCIATED METHODS FOR TREATINGNEOPLASMS” filed Dec. 11, 2018, now U.S. Pat. No. 10,434,082, which is acontinuation-in-part of U.S. application Ser. No. 16/025,640, entitled“METHOD FOR TREATING INFECTIOUS DISEASES WITH ISOTHIOCYANATE FUNCTIONALCOMPOUNDS” filed Jul. 2, 2018, now U.S. Pat. No. 10,335,387, which is acontinuation-in-part of U.S. application Ser. No. 15/838,444, entitled“METHOD FOR TREATING BLADDER CANCER” filed Dec. 12, 2017, now U.S. Pat.No. 10,111,852, which is a continuation of U.S. application Ser. No.15/423,869, entitled “METHOD FOR TREATING BLADDER CANCER” filed Feb. 3,2017, now U.S. Pat. No. 9,839,621, which is a continuation-in-part ofU.S. application Ser. No. 14/867,626, entitled “METHOD FOR TREATING SKINCANCER,” filed Sep. 28, 2015, now U.S. Pat. No. 9,642,827, which is acontinuation of U.S. application Ser. No. 14/867,585, entitled “METHODFOR TREATING SKIN CANCER,” filed Sep. 28, 2015, now U.S. Pat. No.9,636,320, which is a continuation of U.S. application Ser. No.14/519,510, entitled “METHOD FOR TREATING SKIN CANCER,” filed Oct. 21,2014, now U.S. Pat. No. 9,504,667, which is a continuation of U.S.application Ser. No. 13/952,236, entitled “METHOD FOR TREATING SKINCANCER,” filed Jul. 26, 2013, now U.S. Pat. No. 8,865,772, which claimsthe benefit of U.S. Provisional Application Ser. No. 61/676,093,entitled “METHOD FOR TREATING SKIN CANCER,” filed Jul. 26, 2012—whichare hereby incorporated herein by reference in their entirety, includingall references cited therein.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not applicable.

REFERENCE TO A SEQUENCE LISTING

Not applicable.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The present invention relates in general to medicament formulations andmethods for treating neoplasms, and, more particularly, to methods fortreating benign neoplasms, in situ neoplasms, malignant neoplasms,and/or neoplasms of uncertain or unknown behavior by administering anisothiocyanate functional compound augmented with a secondary,antineoplastic medicament to a patient having one or more neoplasms. Thepresent invention also relates to the prophylactic administration offormulations disclosed herein.

2. Background Art

Neoplasms are ubiquitous—many forms of which have no known effectivetreatment and/or cure, and most of the current treatments for neoplasms,including, but not limited to, malignant neoplasms or cancers arereplete with drawbacks, side effects, and/or toxicity issues.

It is therefore an object of the present invention to provide new,useful, and nonobvious medicament formulations and methods for treatingand/or preventing benign neoplasms, in situ neoplasms, malignantneoplasms, and/or neoplasms of uncertain or unknown behavior.

These and other objects of the present invention will become apparent inlight of the present specification, claims, and drawings.

SUMMARY OF THE INVENTION

The present invention is directed to a medicament formulation,comprising: (a) a first medicament, wherein the first medicamentpreferably comprises an isothiocyanate functional compound/surfactant;and (b) a second medicament, wherein the second medicament preferablycomprises an antineoplastic agent, such as a cytotoxic antineoplasticagent and/or a targeted antineoplastic agent. The therapeutic effectson, for example, malignant neoplasms are believed to be enhanced by thesynergistic effect of the two medicaments/active ingredients.

The present invention is also directed to a method for treating benignneoplasms, in situ neoplasms, malignant neoplasms, and/or neoplasms ofuncertain or unknown behavior, comprising the step of: administering toa patient (e.g., mammal/human) a first medicament, wherein the firstmedicament preferably comprises an isothiocyanate functionalcompound/surfactant, and a second medicament, wherein the secondmedicament preferably comprises secondary, antineoplasticmedicament—such as a cytotoxic antineoplastic agent and/or a targetedantineoplastic agent.

In a preferred embodiment of the present invention, the first and secondmedicaments are collectively and/or independently administered to thepatient orally, intravenously, intramuscularly, intrathecally,cutaneously, subcutaneously, transdermally, sublingually, buccally,rectally, vaginally, ocularly, otically, and/or nasally. In thisembodiment, the amount of isothiocyanate functional surfactantadministered to the patient preferably ranges from approximately 0.5nmol/cm2 to approximately 10 μmol/cm2 when topically administered.

In another preferred embodiment of the present invention, the weightratio of the first medicament to the second medicament is approximately1:1,000,000 to 1,000,000:1, 1:100,000 to 100,000:1, 1:10,000 to10,000:1, 1:1,000 to 1,000:1, 1:500 to 500:1, 1:100 to 100:1, 1:10 to10:1, and/or 1:1.

DETAILED DESCRIPTION OF THE INVENTION

While this invention is susceptible of embodiment in many differentforms, there is shown in the drawings and/or described herein in detailseveral specific embodiments with the understanding that the presentdisclosure is to be considered as an exemplification of the principlesof the invention and is not intended to limit the invention to theembodiments illustrated.

In accordance with the present invention, medicament formulations aredisclosed herein, comprising: (a) a first medicament, wherein the firstmedicament preferably comprises an isothiocyanate functionalcompound/surfactant; and (b) a second medicament, wherein the secondmedicament preferably comprises an antineoplastic agent, such as acytotoxic antineoplastic agent and/or a targeted antineoplastic agent.The medicament formulations of the present invention are used to treatand/or prevent, for example, benign neoplasms, in situ neoplasms,malignant neoplasms, and/or neoplasms of uncertain or unknown behavior.The therapeutic effects on, for example, malignant neoplasms or cancersare believed to be enhanced by the synergistic effect of the twomedicaments/active ingredients. In particular, and especially fortopical applications, the isothiocyanate functional compound/surfactant(i.e., the first medicament) permeates the skin and makes it easier forthe second medicament or other actives (e.g., tertiary medicament,etcetera) to penetrate the skin. Once the isothiocyanate functionalcompound/surfactant has intercalated with the lipid bilayers of thestratum corneum, this leads to a looser, more permeablestructure/environment. Unlike other presently available isothiocyanatecompounds, the isothiocyanate functional compounds of the presentinvention are surfactants—and many are advantageously C12 surfactantsand/or +/−C2. Therefore, it not only makes it easier for otherantineoplastic agents and/or cancer drugs to penetrate into the skin, italso contributes its own antineoplastic activity as an isothiocyanate,hence the synergism.

In one embodiment, the present invention is directed to a method fortreating and/or preventing benign neoplasms, in situ neoplasms,malignant neoplasms, and/or neoplasms of uncertain or unknown behavior,comprising the step of: administering to a patient (e.g., mammal/human)a first medicament, wherein the first medicament preferably comprises anisothiocyanate functional compound/surfactant, and a second medicament,wherein the second medicament preferably comprises secondary,antineoplastic medicament or other medicament. Preferably, theisothiocyanate functional surfactant comprises one or moreisothiocyanate functional groups associated with an aliphatic and/oraromatic carbon atom of the isothiocyanate functional surfactant. Itwill be understood that isothiocyanate functional surfactants,regardless of their ordinary meaning, are defined herein as a surfactanthaving an isothiocyanate functional group associated therewith. It willbe yet further understood that the term “associated” as used herein inchemical context, regardless of its ordinary meaning, is defined hereinas attached, a covalent bond, a polar covalent bond, an ionic bond, ahydrogen bond, van der Waals forces, electrostatic interaction, directlyand/or indirectly linked, etcetera.

The term surfactant derives from contraction of the termssurface-active-agent and is defined herein as a molecule and/or group ofmolecules which are able to modify the interfacial properties of theliquids (aqueous and non-aqueous) in which they are present. Thesurfactant properties of these molecules reside in their amphiphiliccharacter which stems from the fact that each surfactant molecule hasboth a hydrophilic moiety and a hydrophobic (or lipophilic) moiety, andthat the extent of each of these moieties is balanced so that atconcentrations at or below the critical micelle concentration (i.e.,CMC) they generally concentrate at the air-liquid interface andmaterially decrease the interfacial tension. For example, sodium saltsof saturated carboxylic acids are extremely soluble in water up to C8length and are thus not true surfactants. They become less soluble inwater from C9 up to C18 length, the domain of effective surfactants forthis class of compounds. The carboxylic acids (fatty acids) can beeither saturated or unsaturated starting from C16 chain lengths.

Without being bound by any one particular theory, it is believed thatthe isothiocyanate functional surfactants disclosed herein facilitatetreatment of neoplasms and/or neoplastic conditions by, elevating phaseII enzymes (e.g., HAD(P)H quinine oxidoreductase) which are believed to,among other things regulate inflammatory responses within the body.

In accordance with the present invention, the isothiocyanate functionalsurfactants may be used as an administered leave-on/leave-in product inwhich one or more surfactants remain on/in the body and are notimmediately and/or ever removed from the body. Alternatively, theisothiocyanate functional surfactants of the present invention may beused in an administer and remove fashion. For either case, it ispreferred that the isothiocyanate functional surfactants be generallymild to human body (e.g., non-irritating or low-irritating). Inparticular, anionic N-alkanoyl surfactants derived from amino acids areespecially preferred because, while not completely predictable, theyhave a tendency to be mild. The methods of preparation detailed in thisinvention employ, but are not limited to, amino acids that possess atleast two amine functionalities, at least one of which is converted toan N-alkanoyl functionality, and at least one of which is converted intoisothiocyanate functionality. The amino acids include, but are notlimited to, the α-amino acids lysine, ornithine, 2,4-diaminobutanoicacid, 2,3-diaminopropionic acid, 2,7-diaminoheptanoic acid, and2,8-diaminooctanoic acid. Additionally, amino acids other than α-aminoacids may be employed, such as β-amino acids, etcetera. It will beunderstood that amino acid derived surfactants are preferred due totheir mild nature, but any one of a number of other surfactants arelikewise contemplated for use in accordance with the present invention.

Methods for preparing isothiocyanate functional surfactants and/or theirprecursors can involve, but are not limited to, conversion of an aminefunctionality to an isothiocyanate functionality. The methods ofconversion of amine functionalities to isothiocyanate functionalitiesinclude, but are not limited to: (1) reaction with carbon disulfide toyield an intermediate dithiocarbamate, followed by reaction withethylchloroformate or its functional equivalent such asbis(trichloromethyl)-carbonate, trichloromethyl chloroformate, orphosgene; (2) reaction with thiophosgene; (3) reaction with1,1′-thiocarbonyldiimidizole; (4) reaction with phenylthiochloroformate;(5) reaction with ammonium or alkali metal thiocyanate to prepare anintermediate thiourea followed by cleaving to the isothiocyanate viaheating; and (6) reaction with an isothiocyanato acyl halide[SCN—(CH₂)_(n)—CO—Cl]. The resulting isothiocyanate functionalsurfactant, depending on the method of preparation, can be isolated as apure material or as a mixture with other surfactants. The resultingisothiocyanate functional surfactant, depending on the method ofpreparation, can be isolated and used directly in nonionic form, anionicform, cationic form, zwitterionic (amphoteric) form, and/or in a neutralsurfactant-precursor form in combination with a base such as sodiumhydroxide or triethanol amine if the neutral surfactant-precursor formpossesses a protonated carboxylic acid group such that reaction(deprotonation) with the base converts the neutral surfactant-precursorform to an anionic surfactant, or in neutral surfactant-precursor formin combination with an acid if the neutral surfactant-precursor formpossess amine functionality such that reaction (protonation) with theacid converts the neutral surfactant-precursor form to a cationicsurfactant.

In accordance with the present invention the step of administeringcomprises, but is not limited to, systemic administration, localinjection, regional injection, spraying, applying, dripping, dabbing,rubbing, blotting, dipping, and any combination thereof.

In one preferred embodiment of the present invention, the isothiocyanatefunctional surfactant is removed from body and/or affected area (e.g.,in, on, and/or proximate to a neoplasm) after a period of time. Such aperiod comprises, but is not limited to, seconds (e.g., 1 second, 2seconds, 5 seconds, 10 seconds, 15 seconds, 20 seconds, 30 seconds, 45seconds, and 60 seconds), minutes (e.g., 1 minute, 2 minutes, 5 minutes,10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, and 60minutes), hours (e.g., 1 hour, 2 hours, 4 hours, 5 hours, 8 hours, 10hours, 15 hours, 24 hours, 36 hours, 48 hours, and 60 hours), days(e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days,14 days, 21 days, 30 days), etcetera. It will be understood that thestep of removing preferably occurs via purging, rinsing, wiping, and/orextracting—just to name a few.

Depending upon the subject and/or the severity of the condition and/ordisease, multiple administrations may be necessary. As such, the stepsof administering and/or removing the isothiocyanate functionalsurfactant may be repeated one or a plurality of times.

First Medicament

In a preferred embodiment of the present invention, the isothiocyanatefunctional surfactant comprises a lysine derivative, wherein the lysinederivative comprises an α-nitrogen and a ε-nitrogen, and wherein analkyl and/or alkanoyl substituent comprising at least approximately 8carbon atoms is associated with the α-nitrogen, and further wherein atleast one isothiocyanate functional group is associated with theε-nitrogen.

In one embodiment of the present invention, the isothiocyanatefunctional surfactant is represented by the following chemicalstructure:

wherein the protonated form of the surfactant comprises a non-polarmoiety (NP) and a polar moiety (P), and wherein at least oneisothiocyanate functional group (NCS) is associated with the polarand/or non-polar moiety.

In accordance with a preferred embodiment of the present invention, theprotonated form of the isothiocyanate functional surfactant isrepresented by the following chemical structure:

wherein R₁ comprises an alkyl, cycloalkyl, polycycloalkyl,heterocycloalkyl, aryl, alkaryl, aralkyl, alkoxy, alkanoyl, aroyl,alkenyl, alkynyl and/or cyano group containing approximately 1 toapproximately 25 carbon atom(s), wherein the carbon atom(s) may be alinking group to, or part of, a halogen, a N, O, and/or S containingmoiety, and/or one or more functional groups comprising alcohols,esters, ammonium salts, phosphonium salts, and combinations thereof; alinkage to a dimer; a linkage to an oligomer; and/or a linkage to apolymer; wherein R₂ comprises NCS; and wherein R₃-R₅ are the same ordifferent and comprise H; OH; an alkyl, cycloalkyl, polycycloalkyl,heterocycloalkyl, aryl, alkaryl, aralkyl, alkoxy, alkanoyl, aroyl,alkenyl, alkynyl and/or cyano group containing approximately 1 toapproximately 25 carbon atom(s), wherein the carbon atom(s) may be alinking group to, or part of, a halogen, a N, O, and/or S containingmoiety, and/or one or more functional groups comprising alcohols,esters, ammonium salts, phosphonium salts, and combinations thereof; alinkage to a dimer; a linkage to an oligomer; and/or a linkage to apolymer with the proviso that at least one of R₃-R₅ comprise an alkyl,cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl, alkaryl, aralkyl,alkoxy, alkanoyl, aroyl, alkenyl, alkynyl and/or cyano group containingapproximately 8 to approximately 25 carbon atom(s).

In a preferred embodiment of the present invention, the protonated formof the isothiocyanate functional surfactant is represented by thefollowing chemical structure:

wherein R₁ is selected from the group consisting of an alkyl groupcontaining 1 to 25 carbon atom(s); wherein R₂ is selected from the groupconsisting of NCS; and wherein R₃-R₅ are each independently selectedfrom the group consisting of H; OH; and an alkyl, and alkanoyl groupcontaining 1 to 25 carbon atom(s) with the proviso that at least one ofR₃-R₅ is selected from the group consisting of an alkyl, and alkanoyl,group containing 8 to 25 carbon atoms.

In another preferred embodiment of the present invention, the protonatedform of the isothiocyanate functional surfactant is represented by thefollowing chemical structure:

wherein X comprises an integer ranging from approximately 1 toapproximately 25, and wherein Y comprises an integer ranging fromapproximately 6 to approximately 25. In this embodiment, the protonatedform of the isothiocyanate functional surfactant is preferablyrepresented by the following chemical structure:

In yet another preferred embodiment of the present invention, theprotonated form of the isothiocyanate functional surfactant isrepresented by at least one of the following chemical structures:

In another preferred embodiment of the present invention, theisothiocyanate functional surfactant is represented by the followingchemical structure:

wherein R₁ comprises an alkyl, cycloalkyl, polycycloalkyl,heterocycloalkyl, aryl, alkaryl, aralkyl, alkoxy, alkanoyl, aroyl,alkenyl, alkynyl and/or cyano group containing approximately 1 toapproximately 25 carbon atom(s), wherein the carbon atom(s) may be alinking group to, or part of, a halogen, a N, O, and/or S containingmoiety, and/or one or more functional groups comprising alcohols,esters, ammonium salts, phosphonium salts, and combinations thereof; alinkage to a dimer; a linkage to an oligomer; and/or a linkage to apolymer; wherein R₂ comprises NCS; wherein R₃-R₅ are the same ordifferent and comprise H; OH; an alkyl, cycloalkyl, polycycloalkyl,heterocycloalkyl, aryl, alkaryl, aralkyl, alkoxy, alkanoyl, aroyl,alkenyl, alkynyl and/or cyano group containing approximately 1 toapproximately 25 carbon atom(s), wherein the carbon atom(s) may be alinking group to, or part of, a halogen, a N, O, and/or S containingmoiety, and/or one or more functional groups comprising alcohols,esters, ammonium salts, phosphonium salts, and combinations thereof; alinkage to a dimer; a linkage to an oligomer; and/or a linkage to apolymer with the proviso that at least one of R₃-R₅ comprise an alkyl,cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl, alkaryl, aralkyl,alkoxy, alkanoyl, aroyl, alkenyl, alkynyl and/or cyano group containingapproximately 8 to approximately 25 carbon atom(s), wherein X comprisesa counter cation such as, but not limited to, alkali metals, alkalineearth metals, transition metals, s-block metals, d-block metals, p-blockmetals, NZ₄ ⁺, wherein Z comprises, H, R₆, OR₆, and wherein R₆ comprisesan alkyl, cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl, alkaryl,aralkyl, alkoxy, alkanoyl, aroyl, alkenyl, alkynyl and/or cyano groupcontaining approximately 1 to approximately 25 carbon atom(s), whereinthe carbon atom(s) may be a linking group to, or part of, a halogen, aN, O, and/or S containing moiety, and/or one or more functional groupscomprising alcohols, esters, ammonium salts, phosphonium salts, andcombinations thereof; a linkage to a dimer; a linkage to an oligomer;and/or a linkage to a polymer.

In yet another preferred embodiment of the present invention, theisothiocyanate functional surfactant is represented by the followingchemical structure:

wherein R₁ is selected from the group consisting of an alkyl groupcontaining 1 to 25 carbon atom(s); wherein R₂ is selected from the groupconsisting of NCS; and wherein R₃-R₅ are each independently selectedfrom the group consisting of H; OH; and an alkyl, and alkanoyl groupcontaining 1 to 25 carbon atom(s) with the proviso that at least one ofR₃-R₅ is selected from the group consisting of an alkyl, and alkanoyl,group containing 8 to 25 carbon atoms; and wherein X comprises a countercation.

In accordance with the present invention, the isothiocyanate functionalsurfactant may also be associated with one or more additionalsurfactants, wherein the additional surfactants are selected from atleast one of the group comprising a non-ionic surfactant, an anionicsurfactant, a cationic surfactant, a zwitterionic surfactant, andcombinations thereof.

Non-limiting examples of preferred anionic surfactants include taurates;isethionates; alkyl and alkyl ether sulfates; succinamates; alkylsulfonates, alkylaryl sulfonates; olefin sulfonates; alkoxy alkanesulfonates; sodium and potassium salts of fatty acids derived fromnatural plant or animal sources or synthetically prepared; sodium,potassium, ammonium, and alkylated ammonium salts of alkylated andacylated amino acids and peptides; alkylated sulfoacetates; alkylatedsulfosuccinates; acylglyceride sulfonates, alkoxyether sulfonates;phosphoric acid esters; phospholipids; and combinations thereof.Specific anionic surfactants contemplated for use include, but are by nomeans limited to, ammonium cocoyl isethionate, sodium cocoylisethionate, sodium lauroyl isethionate, sodium stearoyl isethionate,sodium lauroyl sarcosinate, sodium cocoyl sarcosinate, sodium laurylsarcosinate, disodium laureth sulfosuccinate, sodium laurylsulfoacetate, sodium cocoyl glutamate, TEA-cocoyl glutamate, TEA cocoylalaninate, sodium cocoyl taurate, potassium cetyl phosphate.

Non-limiting examples of preferred cationic surfactants includealkylated quaternary ammonium salts R₄NX; alkylated amino-amides(RCONH—(CH₂)_(n))NR₃X; alkylimidazolines; alkoxylated amines; andcombinations thereof. Specific examples of anionic surfactantscontemplated for use include, but are by no means limited to, cetylammonium chloride, cetyl ammonium bromide, lauryl ammonium chloride,lauryl ammonium bromide, stearyl ammonium chloride, stearyl ammoniumbromide, cetyl dimethyl ammonium chloride, cetyl dimethyl ammoniumbromide, lauryl dimethyl ammonium chloride, lauryl dimethyl ammoniumbromide, stearyl dimethyl ammonium chloride, stearyl dimethyl ammoniumbromide, cetyl trimethyl ammonium chloride, cetyl trimethyl ammoniumbromide, lauryl trimethyl ammonium chloride, lauryl trimethyl ammoniumbromide, stearyl trimethyl ammonium chloride, stearyl trimethyl ammoniumbromide, lauryl dimethyl ammonium chloride, stearyl dimethyl cetylditallow dimethyl ammonium chloride, dicetyl ammonium chloride, dilaurylammonium chloride, dilauryl ammonium bromide, distearyl ammoniumchloride, distearyl ammonium bromide, dicetyl methyl ammonium chloride,dicetyl methyl ammonium bromide, dilauryl methyl ammonium chloride,distearyl methyl ammonium chloride, distearyl methyl ammonium bromide,ditallow dimethyl ammonium chloride, ditallow dimethyl ammonium sulfate,di(hydrogenated tallow) dimethyl ammonium chloride, di(hydrogenatedtallow) dimethyl ammonium acetate, ditallow dipropyl ammonium phosphate,ditallow dimethyl ammonium nitrate, di(coconutalkyl)dimethyl ammoniumchloride, di(coconutalkyl)dimethyl ammonium bromide, tallow ammoniumchloride, coconut ammonium chloride, stearamidopropyl PG-imoniumchloride phosphate, stearamidopropyl ethyldimonium ethosulfate,stearimidopropyldimethyl (myristyl acetate) ammonium chloride,stearamidopropyl dimethyl cetearyl ammonium tosylate, stearamidopropyldimethyl ammonium chloride, stearamidopropyl dimethyl ammonium lactate,ditallowyl oxyethyl dimethyl ammonium chloride, behenamidopropyl PGdimonium chloride, dilauryl dimethyl ammonium chloride, distearlydimethyl ammonium chloride, dimyristyl dimethyl ammonium chloride,dipalmityl dimethyl ammonium chloride, distearyl dimethyl ammoniumchloride, stearamidoproyl PG-dimonium chloride phosphate,stearamidopropyl ethyldiammonium ethosulfate, stearamidopropyl dimethyl(myristyl acetate) ammonium chloride, stearimidopropyl dimethyl cetarylammonium tosylate, stearamido propyl dimethyl ammonium chloride,stearamidopropyl dimethyl ammonium lactate.

Non-limiting examples of preferred non-ionic surfactants includealcohols, alkanolamides, amine oxides, esters (including glycerides,ethoxylated glycerides, polyglyceryl esters, sorbitan esters,carbohydrate esters, ethoxylated carboxylic acids, phosphoric acidtriesters), ethers (including ethoxylated alcohols, alkyl glucosides,ethoxylated polypropylene oxide ethers, alkylated polyethylene oxides,alkylated polypropylene oxides, alkylated PEG/PPO copolymers), siliconecopolyols. Specific examples of non-ionic surfactants contemplated foruse include, but are by no means limited to, cetearyl alcohol,ceteareth-20, nonoxynol-9, C12-15 pareth-9, POE(4) lauryl ether,cocamide DEA, glycol distearate, glyceryl stearate, PEG-100 stearate,sorbitan stearate, PEG-8 laurate, polyglyceryl-10 trilaurate, laurylglucoside, octylphenoxy-polyethoxyethanol, PEG-4 laurate, polyglyceryldiisostearate, polysorbate-60, PEG-200 isostearyl palmitate, sorbitanmonooleate, polysorbate-80.

Non-limiting examples of preferred zwitterionic or amphotericsurfactants include betaines; sultaines; hydroxysultaines, amidobetaines, amidosulfo betaines; and combinations thereof. Specificexamples of amphoteric surfactants contemplated for use include, but areby no means limited to, cocoamidopropyl sultaine, cocoamidopropylhydroxyl sultaine, cocoamidopropylbetaine, coco dimethyl carboxymethylbetaine, lauryl dimethyl carboxymethyl betaine, lauryl dimethylalphacarboxyethyl betaine, cetyl dimethyl carboxymethyl betaine, cetyldimethyl betaine, lauryl (2-bishydroxy) carboxymethyl betaine, stearylbis-(2-hydroxyethyl) carboxymethyl betaine, oelyl dimethylgamma-carboxypropyl betaine, lauryl bis-(2-hydroxypropyl)alphacarboxymethyl betaine, coco dimethyl sulfopropyl betaine, stearyldimethyl sulfopropyl betaine, lauryl dimethyl sulfoethyl betaine, laurylbis(2-hydroxyethyl) sulfopropyl betaine, oleyl betaine, cocamidopropylbetaine.

Second Medicament

In a preferred embodiment of the present invention, the secondmedicament comprises a cytotoxic antineoplastic agent selected from thegroup comprising nucleoside analogues (e.g., azacytidine, capecitabine,carmofur, cladribine, clofarabine, cytarabine, decitabine, floxuridine,fludarabine, fluorouracil, gemcitabine, mercaptopurine, nelarabine,pentostatin, tegafur, tioguanine, etcetera), antifolates (e.g.,methotrexate, pemetrexed, raltitrexed, etcetera), antimetabolites (e.g.,hydroxycarbamide, etcetera), topoisomerase inhibitors (e.g., irinotecan,topotecan, etcetera), anthracyclines (e.g., daunorubicin, doxorubicin,epirubicin, idarubicin, mitoxantrone, valrubicin, etcetera),podophyllotoxins (e.g., etoposide, teniposide, etcetera), taxanes (e.g.,cabazitaxel, docetaxel, paclitaxel, etcetera), vinca alkaloids (e.g.,vinblastine, vincristine, vindesine, vinflunine, vinorelbine, etcetera),alkylating agents (e.g., bendamustine, busulfan, carmustine,chlorambucil, chlormethine, cyclophosphamide, dacarbazine, fotemustine,ifosfamide, lomustine, melphalan, streptozotocin, temozolomide,etcetera), metal/platinum compounds (e.g., carboplatin, cisplatin,nedaplatin, oxaliplatin, etcetera), and/or other non-categorizedcytotoxic antineoplastic agents (e.g., altretamine, bleomycin,bortezomib, dactinomycin, estramustine, ixabepilone, mitomycin,procarbazine, etcetera).

In another preferred embodiment of the present invention, the cytotoxicantineoplastic agents are represented by one or more of the followingchemical structures:

In a preferred embodiment of the present invention, the secondmedicament comprises a targeted antineoplastic agent selected from thegroup comprising monoclonal antibodies (e.g., alemtuzumab, bevacizumab,cetuximab, denosumab, gemtuzumab ozogamicin, ibritumomab tiuxetan,ipilimumab, nivolumab, ofatumumab, panitumumab, pembrolizumab,pertuzumab, rituximab, tositumomab, trastuzumab, etcetera), tyrosinekinase inhibitors (e.g., afatinib, aflibercept, axitinib, bosutinib,crizotinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib,nilotinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib,sunitinib, vandetanib, etcetera), mTOR inhibitors (e.g., everolimus,temsirolimus, etcetera), retinoids (e.g., alitretinoin, bexarotene,isotretinoin, tamibarotene, tretinoin, etcetera), immunomodulatoryagents (e.g., lenalidomide, pomalidomide, thalidomide, etcetera),histone deacetylase inhibitors (e.g., romidepsin, valproate, vorinostat,etcetera), and/or other non-categorized targeted antineoplastic agents(e.g., anagrelide, arsenic trioxide, asparaginase, bcg vaccine,denileukin diftitox, vemurafenib, etcetera).

In another preferred embodiment of the present invention, the targetedantineoplastic agents are represented by one or more of the followingchemical structures:

In one embodiment of the present invention, the second medicamentcomprises at least one of a DNA-effecting or influencing anti-cancermedicament, a kinase-inhibiting anti-cancer medicament, an anti-androgenmedicament (e.g., bicalutamide, flutamide, nilutamide, etcetera), and/ora hormonal anti-cancer medicament. In this embodiment, the secondmedicaments are preferably represented by one or more of the followingchemical structures:

Additional, non-limiting examples of secondary and/or tertiarymedicaments include those disclosed in U.S. Pat. No. 10,010,520,entitled “COMBINED APPLICATION OF ISOTHIOCYANATE COMPOUND ANDANTI-CANCER MEDICINE,” which is hereby incorporated herein by referencein its entirety, including all references cited therein.

In further accordance with the present invention, the first and secondmedicaments may optionally be incorporated into a formulation comprisingone or more polar and/or non-polar solvents. Preferably, the solventcomprises a hydrocarbon and/or silicone oil that is generallynon-hygroscopic and/or generally hydrophobic. Suitable examples,include, silicone-based solvents and/or fluids, mineral oil, vegetableoils, squalene (i.e., 2,6,10,15,19,23-hexamethyltetracosane)—just toname a few.

Additional agents that are used in oncology are likewise contemplatedfor use in the formulations and treatment methods of the presentinvention, including, but not limited to, antiemetics, hematopoieticgrowth factors (e.g., erythropoietin, GCSF, oprelvekin, pegfilgrastim,GMCSF, etcetera), other marrow stimulating agents (e.g., eltrombopag,plerixafor, romiplostim, etcetera), immunosuppressants (e.g.,basiliximab, cyclosporine, mycophenolic acid, etctera), anti-complementtherapy (e.g., eculizumab, etctera), bone resorption modifiers (e.g.,calcitonin, cinacalcet, denosumab, pamidronate, zoledronate, etctera),toxicity modifiers (e.g., allopurinol, amifostine, dexrazoxane,glucarpidase, methylene blue, mesna, palifermin, rasburicase, etctera),medications for infections, anticoagulants and thrombolytic agents suchas alteplase for central venous access device clearance, replacementtherapies (e.g., folate, intravenous iron, vitamin B₁₂, etctera), ironbinding agents (e.g., deferasirox, deferiprone, deferoxamine, etctera)and/or diagnostic agents (e.g., fluciclovine).

In a preferred embodiment of the present invention, the first and secondmedicaments are collectively and/or independently administered to thepatient orally, intravenously, intramuscularly, intrathecally,cutaneously, subcutaneously, transdermally, sublingually, buccally,rectally, vaginally, ocularly, otically, and/or nasally. In thisembodiment, the amount of isothiocyanate functional surfactantadministered to the patient preferably ranges from approximately 0.5nmol/cm2 to approximately 10 μmol/cm2 when topically administered.

In another preferred embodiment of the present invention, the weightratio of the first medicament to the second medicament is approximately1:1,000,000 to 1,000,000:1, 1:100,000 to 100,000:1, 1:10,000 to10,000:1, 1:1,000 to 1,000:1, 1:500 to 500:1, 1:100 to 100:1, 1:10 to10:1, and/or 1:1.

The invention is further described by the following examples.

Example I Preparation of a mixture ofN_(α)-lauroyl-N_(ε)-isothiocyanato-L-Lysine withN_(α),N_(ε)-bis-lauroyl-L-lysine

A 1 liter beaker equipped with an overhead mechanical stainless steelpaddle stirrer was charged with 100 mL of 1 M NaOH (0.100 mol). Stirringwas begun and the beaker cooled to −5° C. to −10° C. using a salt/icebath. Next, 23.4 g (0.100 mol) of N_(ε)-benzylidene-L-lysine (preparedvia the method of Bezas, B and Zervas, L., JACS, 83, 1961, 719-722) wasadded. Immediately afterward and while keeping the solution cold, 140 mL(0.140 mol) of precooled (in a salt/ice bath) 1 M NaOH and 26.1 mL oflauroyl chloride was added in two equal portions over a period of 6minutes. The mixture was stirred for 10 more minutes at −5 to −10° C.,then the ice bath was removed and the reaction mixture allowed to stirfor another 1 hour while warming to room temperature. Next, the reactionmixture was cooled using a salt/ice bath and then sufficientconcentrated HCl was added to adjust the pH to 7.5-7.8. With the pH at7.8-7.8 and with continued cooling and stirring, 4.6 mL (60% ofstoichiometric, 0.068 mol) of thiophosgene was added drop-wise via anadditional funnel over the period of 1 hour. During this time,sufficient 1 M NaOH was added to maintain a pH range between 7.5-7.8.After the thiophosgene addition was complete, additional 1 M NaOH wasadded as necessary until the pH stabilized in 7.5-7.8 range. Next,sufficient 30% NaOH was added to adjust the pH to approximately 8.5.Next, 12 mL (0.051 mol) of lauroyl chloride was rapidly added, followedby sufficient 1 M NaOH to keep the pH in the range of 8.00-8.50. Next,sufficient concentrated HCl was added to adjust the pH to 1.5. Thereaction mixture was filtered via vacuum filtration, and the precipitatewashed with dilute HCl (pH=2). The product, a white moist solid, wasdried in vacuo while heating to 60° C. 45.19 g of white solid productwas recovered, a mixture of predominantlyN_(α)-lauroyl-N_(ε)-isothiocyanato-L-lysine andN_(α),N_(ε)-bis-lauroyl-L-lysine (determined via LC-MS analysis). Bothcompounds in this mixture can be simultaneously converted into anionic(carboxylate) surfactants via reaction with aqueous NaOH to yield aclear aqueous solution of the surfactants.

Example II Preparation of PureN_(α)-lauroyl-N_(ε)-isothiocyanato-L-Lysine Step 1: Preparation ofN_(α)-lauroyl-N_(ε)-carbobenzoxy-L-Lysine

60.0 g of N_(ε)-cbz-L-Lysine (cbz is carbobenzoxy) purchased fromAtomole Scientific Company, LTD was added to a three-liter beaker alongwith 1200 mL of RO water and the mixture was stirred. Next, 39 mL of 30%aqueous NaOH was added, resulting in dissolution of theN_(ε)-cbz-L-Lysine. The resulting solution was cooled in an ice bath andthen 52.5 mL of lauroyl chloride was added. The ice bath was removed 30minutes later, and stirring continued for an additional six hours, atwhich time 18 mL of concentrated hydrochloric acid was added. Thereaction mixture was then filtered via vacuum filtration, the whitesolid product washed with 1 M aqueous HCl, and then the solid productwas dried in vacuo while heated to approximately 85° C. 96.5 g of drywhite solid product was obtained. The product can be further purified bydissolving it in methanol, filtering off any insoluble precipitate, andremoving the methanol in vacuo to recover a white solid product (mp99.5-103.0° C.)

Step 2: Preparation of N_(α)-lauroyl-N_(ε)-ammonium chloride-L-Lysine

10.0 g of N_(α)-lauroyl-N_(ε)-carbobenzoxy-L-Lysine was weighed into aone liter Erlenmeyer flask equipped with a magnetic stir bar. 150 mL ofconcentrated hydrochloric acid was added and the solution was stirredand heated in an oil bath to 104° C., then allowed to cool with the oilbath back to room temperature. The solution was then cooled to 9° C. forapproximately four hours, during which time a large mass of whiteprecipitate formed. The reaction mixture was filtered in vacuo andrinsed with a small amount of cold 1 M HCl. The white solid reactionproduct was then dried in vacuo while being heated to 78° C., yielding7.89 g of white solid product (mp 191-193° C.).

Step 3: Preparation of N_(α)-lauroyl-N_(ε)-isothiocyanato-L-Lysine

0.46 mL of thiophosgene was added to 30 mL of dichloromethane in a 125mL Erlenmeyer flask equipped with a magnetic stir bar. To this solutionwas drop wise added over 15 minutes a solution consisting of 2.00 gN_(α)-lauroyl-N_(ε)-ammonium chloride-L-Lysine, 10 mL RO water, and 2.7mL 20% aqueous NaOH. Stirring was continued for an additional 30minutes, after which sufficient concentrated hydrochloric acid was addedto lower the pH to 1 as indicated by testing with pHydrion paper. Thereaction solution was then transferred into a separatory funnel and thebottom turbid dichloromethane layer was isolated and dried withanhydrous magnesium sulfate and gravity filtered. To the filtrate wasadded 50 mL of hexanes. The solution was then concentrated via removalof 34 mL of solvent via trap-to-trap distillation and then placed in a−19° C. freezer. A mass of white precipitate formed after a few hoursand was isolated via vacuum filtration and then dried in vacuo for 2hours. 1.130 g of a slightly off white solid powder product was obtained[mp 37.0-39.0° C.; IR (cm⁻¹), 3301sb, 2923s, 2852s, 2184m, 2099s, 1721s,1650s, 1531s, 1456m, 1416w, 1347m, 1216m, 1136w].

The oils and/or solvents employed hereinabove are provided for thepurposes of illustration, and are not to be construed as limiting theinvention in any way. As such, the oils may be liquid, solid, or gel,and may be synthetic or of natural origin and include but are notlimited to waxes, esters, lipids, fats, glycerides, cyclic silicones,linear silicones, crosslinked silicones, alkylsilicones, siliconecopolyols, alkylated silicone copolyols, and/or hydrocarbons, and/orethoxylated versions of all of these.

The foregoing description merely explains and illustrates the inventionand the invention is not limited thereto except insofar as the appendedclaims are so limited, as those skilled in the art who have thedisclosure before them will be able to make modifications withoutdeparting from the scope of the invention.

While certain embodiments have been illustrated and described, it shouldbe understood that changes and modifications can be made therein inaccordance with ordinary skill in the art without departing from thetechnology in its broader aspects as defined in the following claims.

The embodiments, illustratively described herein may suitably bepracticed in the absence of any element or elements, limitation orlimitations, not specifically disclosed herein. Thus, for example, theterms “comprising,” “including,” “containing,” etcetera shall be readexpansively and without limitation. Additionally, the terms andexpressions employed herein have been used as terms of description andnot of limitation, and there is no intention in the use of such termsand expressions of excluding any equivalents of the features shown anddescribed or portions thereof, but it is recognized that variousmodifications are possible within the scope of the claimed technology.Additionally, the phrase “consisting essentially of” will be understoodto include those elements specifically recited and those additionalelements that do not materially affect the basic and novelcharacteristics of the claimed technology. The phrase “consisting of”excludes any element not specified.

The present disclosure is not to be limited in terms of the particularembodiments described in this application. Many modifications andvariations can be made without departing from its spirit and scope, aswill be apparent to those skilled in the art. Functionally equivalentmethods and compositions within the scope of the disclosure, in additionto those enumerated herein, will be apparent to those skilled in the artfrom the foregoing descriptions. Such modifications and variations areintended to fall within the scope of the appended claims. The presentdisclosure is to be limited only by the terms of the appended claims,along with the full scope of equivalents to which such claims areentitled. It is to be understood that this disclosure is not limited toparticular methods, reagents, compounds compositions or biologicalsystems, which can of course vary. It is also to be understood that theterminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting.

In addition, where features or aspects of the disclosure are describedin terms of Markush groups, those skilled in the art will recognize thatthe disclosure is also thereby described in terms of any individualmember or subgroup of members of the Markush group.

As will be understood by one skilled in the art, for any and allpurposes, particularly in terms of providing a written description, allranges disclosed herein also encompass any and all possible subrangesand combinations of subranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etcetera. As a non-limiting example, each range discussed hereincan be readily broken down into a lower third, middle third and upperthird, etcetera. As will also be understood by one skilled in the artall language such as “up to,” “at least,” “greater than,” “less than,”and the like, include the number recited and refer to ranges which canbe subsequently broken down into subranges as discussed above. Finally,as will be understood by one skilled in the art, a range includes eachindividual member.

All publications, patent applications, issued patents, and otherdocuments referred to in this specification are herein incorporated byreference as if each individual publication, patent application, issuedpatent, or other document was specifically and individually indicated tobe incorporated by reference in its entirety. Definitions that arecontained in text incorporated by reference are excluded to the extentthat they contradict definitions in this disclosure.

Other embodiments are set forth in the following claims.

What is claimed and desired to be secured by Letters Patent of theUnited States is:
 1. A medicament formulation, comprising: a firstmedicament, wherein the first medicament comprises an isothiocyanatefunctional compound; and a second medicament, wherein the secondmedicament comprises an antineoplastic agent.
 2. The medicamentformulation according to claim 1, wherein the isothiocyanate functionalcompound comprises at least one isothiocyanate functional groupassociated with an aliphatic and/or aromatic carbon atom of theisothiocyanate functional compound.
 3. The medicament formulationaccording to claim 1, wherein the isothiocyanate functional compoundcomprises a lysine derivative, wherein the lysine derivative comprisesan α-nitrogen and a ε-nitrogen, and wherein an alkyl and/or alkanoylsubstituent comprising 8 carbon atoms is bound to the α-nitrogen, andfurther wherein the ε-nitrogen forms part of an isothiocyanatefunctional group.
 4. The medicament formulation according to claim 1,wherein the protonated form of the isothiocyanate functional compound isrepresented by the following chemical structure:

wherein R₁ is selected from the group consisting of an alkyl groupcontaining 1 to 25 carbon atom(s); wherein R₂ is selected from the groupconsisting of NCS; and wherein R₃-R₅ are each independently selectedfrom the group consisting of H; OH; and an alkyl group containing 1 to25 carbon atom(s) with the proviso that at least one of R₃-R₅ isselected from the group consisting of an alkyl group containing 8 to 25carbon atoms.
 5. The medicament formulation according to claim 1,wherein the protonated form of the isothiocyanate functional compound isrepresented by the following chemical structure:

wherein R₁ is selected from the group consisting of an alkyl groupcontaining 1 to 25 carbon atom(s); wherein R₂ is selected from the groupconsisting of NCS; and wherein R₃-R₅ are each independently selectedfrom the group consisting of H; OH; and an alkyl, and alkanoyl groupcontaining 1 to 25 carbon atom(s) with the proviso that at least one ofR₃-R₅ is selected from the group consisting of an alkyl, and alkanoyl,group containing 8 to 25 carbon atoms.
 6. The medicament formulationaccording to claim 5, wherein the second medicament comprises at leastone of a cytotoxic antineoplastic agent and a targeted antineoplasticagent.
 7. The medicament formulation according to claim 5, wherein thesecond medicament comprises a cytotoxic antineoplastic agent selectedfrom the group comprising a nucleoside analogue, an antifolate, anantimetabolite, a topoisomerase inhibitor, a anthracycline, apodophyllotoxin, a taxane, a vinca alkaloid, an alkylating agent, and/ora platinum compound.
 8. The medicament formulation according to claim 5,wherein the second medicament comprises a monoclonal antibody, atyrosine kinase inhibitor, an mTOR inhibitor, a retinoid, animmunomodulatory agent, and/or a histone deacetylase inhibitor.
 9. Themedicament formulation according to claim 5, wherein the secondmedicament comprises a DNA-effecting or influencing anti-cancermedicament, a kinase-inhibiting anti-cancer medicament, an anti-androgenmedicament and/or a hormonal anti-cancer medicament.
 10. The medicamentformulation according to claim 5, wherein the second medicamentcomprises bicalutamide.
 11. The medicament formulation according toclaim 5, wherein the second medicament comprises fluorouacil.
 12. Themedicament formulation according to claim 5, wherein the secondmedicament comprises chlormethine.
 13. The medicament formulationaccording to claim 5, wherein the second medicament comprises at leastone of bevacizumab, cetuximab, denosumab, gemtuzumab ozogamicin,ibritumomab tiuxetan, ipilimumab, nivolumab, ofatumumab, panitumumab,pembrolizumab, pertuzumab, rituximab, tositumomab, and trastuzumab. 14.The medicament formulation according to claim 5, wherein the secondmedicament comprises at least one of alitretinoin, bexarotene,isotretinoin, tamibarotene, and tretinoin.